Ibn Al-Haitham Jour. for Pure & Appl. Sci.

33 (2) 2020
 

Ibn Al Haitham Journal

  for Pure and Applied Science

Journal homepage: http://jih.uobaghdad.edu.iq/index.php/j/index

 

A Review: Saccharin Discovery, Synthesis, and Applications

  Ammar A. Razzak Mahmood Sahar B. Al-Juboori 
Department of Pharmaceutical Department of Pharmacy, College of
Chemistry, College of Pharmacy, Al-Rafidain University, Baghdad-
University of Baghdad, Baghdad, Iraq.
Iraq.
kubbaammar1963@gmail.com
Article history: Received 2 October 2019, Accepted 13 January 2020, Published in
April 2020.
Doi: 10.30526/33.2.2442

Abstract
Saccharin is firstly synthesized in 1879. It is a very well-known as an inexpensive
substitute for sugar as it is a non-caloric sweetener. The article shows the properties, use,
metabolism and various synthesis and reactions of saccharine. Moreover, the toxicological
reports explain that saccharin is mostly responsible for the bladder tumors observed in the
male rats, the relationship between the consumption of saccharin and bladder cancer is
afforded by epidemiological studies. The benefit-risk evaluation for saccharin is hardly to
indicate.  Saccharin is a sugar substitute, frequently used either in food industry, or in
pharmaceutical formulations and even in tobacco products. The chemistry of saccharin is
interesting because of it suspected carcinogenous character and the possible use as an antidote
for metal poisoning. It appears prudent to evaluate their main properties and applications
further.

Keywords: Saccharin, Carcinogen, Artificial sweetener, Toxicity, Safety and Photo

isomerization

1. Introduction
1.1. Saccharin
Saccharin is an artificial sweetener with no food energy. It is chemically identified as o-
sulfabenzamide (2,3-dihydro-3-oxobenzisosulfonazole). It is about 400 times as sweet as
sucrose. It is a sulphonamide derivative of toluene, existing as acid saccharin, sodium
saccharin and calcium saccharin [1]. Saccharin is a week organic acid, slightly soluble in
water, with a pKa of 1.6 and chemical formula C7H5NO3S. It has a molar mass of 183.2 g/mol
and a specific gravity of 0.83 g/cm3[2]. Sodium saccharin has high solubility in water and
because of its ease production, it is the most generally used salt. Also, calcium saccharin is
used in different food applications. It is remarkable to know that there is no relation between

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saccharin form and its sweetness intensity. Saccharin and its salts are stable in a solid form,
while in solution it is high hydrolytic thermal, and photo stability. Stability is not affected by
pH and temperatures, usually encountered in food and beverage manufacturing, contain table-
top sweeteners, yogurt, desserts, ice-cream, baked goods, jam, preserves, marmalade, soft
drinks, sweets, mustard and sauces, saccharin can be used in cooking, baking and canning due
to its stability, The acceptable levels of use differ from a hundred to five hundred mg/kg,
based on the food category [3].
Saccharin is decomposed when heated to 380 °C, and all three forms of saccharin emit toxic
fumes of nitrogen oxides and sulfur oxides. During a typical food process, saccharin does not
decompose; however, some hydrolysis happens after prolonged exposure to excessive
conditions pH or temperature when the pH is less than 2.0 and at particularly high
temperatures. The hydrolytic decomposed products of saccharin are (2-sulfobenzoic acid and
2-sulfamoyl benzoic acid). Neither of these compounds displays a sweetener taste [4].

1.2. History of Discovery

Saccharin was discovered in 1878 by a Russian chemist named "Constantine Fahlberg.
During his lab work, he tried to oxidize toluene sulfonamides [5]. Scheme 1. was the first
commercially recognized as a sweet-tasting agent, which was significantly more potent than
sucrose. The first story of saccharin commercial development and its use as a non-caloric
sweetener was reviewed in 2001 by Pearson [6]. (PMC Specialties Group, Inc.), a company
long concerned in the production of saccharin, and more recently by Hicks (Pennsylvania
State University). Today, major companies were involved in saccharin production including
Kaifeng and Shanghai Fortune of China and JMC of South Korea.

Scheme 1. The saccharin production by Remsen–Fahlberg process.

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Scheme 2. Maumee-Synthesis for saccharin manufacture [6].

1.3. Forms of saccharin

1.3.1. Neutral saccharin
IUPAC Name: 1,2-Benzisothiazolin-3-one

   
6
1.3.2. Sodium saccharin
IUPAC Name: 1,2-Benzisothiazolin-3-one, 1,1-dioxide, sodium salt [7].

6a

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1.3.3. Calcium Saccharin
IUPAC Name: 1,2-Benzisothiazolin-3-one, 1,1-dioxide, calcium salt [7].

6b

1.4. Regulatory Aspects

Food ingredients are evaluated and/or regulated by several national and international
organizations. There are various international groups which they assess the use of sweeteners
in the market, including expert scientific committees for example the Scientific Committee on
Food (SCF) of the European Commission (EC), the Joint Expert Committee of Food
Additions (JECFA) of the United Nations Food and Agricultural Organization (FAO) and the
World Health Organization (WHO) [8]. In India Saccharin, Aspartame, Acesulfame k,
Sucralose are allowed under FSSAI, 2011.
Sucrose is generally known as table sugar, and is considered as standard material, to which all
other sweeteners are compared. Sucrose in solution has sweetness perception rating 1, and
other substances are rated relative to this. There are many other alternative sweeteners present
in the market; all with somewhat different sweetness compared to sucrose. Each high-
intensity sweetener has its feature. Manufacturer’s use of an ingredient of sweetener or
combination of elements is the key to product success. The potency of an intense sweetener is
an essential basic characteristic, due to its impact on a diversity of issues involving relative
cost and amounts consumed (the latter impacting safety considerations). Sweetness potency
(more times compared to sucrose) of saccharin is equal 300 [9].

1.5. Physio-chemical Properties

Saccharin is generally found in acid, sodium and calcium forms. All of these are white
solids. Saccharin is considered as a strong acid with pKa of 2.32 [10]. Normally a non-caloric
sweetener should be sufficiently soluble to be utilized in beverages and foods, but, not all
non-caloric sweeteners meet this requirement. It must be mentioned that sweetness intensity
corresponding to 10% sucrose are required, and in several systems (e.g., frozen desserts),
sweetener levels equivalent the sweetness of 15–20% sucrose are desirable. Also, it’s (it is)
observed for many food systems, rapid dissolution is critical to satisfying) with manufacturing
needs. For example, concentrates of the sweetener-flavor system complex are prepared in
carbonated soft drinks, and it is essential that all components quickly dissolve. Thus, for non-
nutritive sweeteners, must display rapid dissolution rates which are very desirable properties.
Besides, a non-caloric sweetener must be stable to hydrolysis plus, to photochemical and
thermal and breakdown to be used in beverages, baked goods, and confectionery [11].
A commercial non-caloric sweetener must have sufficient resistance upon degradation during
hydrolytic, pyrolytic or photochemical processes that may be encountered in food or beverage
applications. Stability is critical for three reasons. First, the product shelf life, during
degradation rate must not be affected. Second, degradation must not produce any unpleasant
taste or odor. And third, any degradation product produced from the use of a non-caloric
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sweeteners that used as food additives, should be safe. In the USA for any food or beverage
application, the safety assessment work for the sweeteners is necessary to carry out if
exposure to the degradation product may exceed 12.5μg/kg, to ensure regulatory approval for
the sweeteners [12]. Table 1. shows the physical properties of saccharin.

Table 1. The physical properties of saccharin.

IUPAC 2-benzothiazol-1,1,3-trione
Other name Benzoic sulfimide
Chemical formula C7H5NO3S
Appearance White cristalline solid
Molar mass 182,999014 g/mol
Density ³ 0,828 g/cm³
Melting Point (228,8-229,7)°C
Solubility in water 3,448 g/L
Solubility in ethanol 32,258 g/L
Solubility in acetone 83,333 g/L
Solubility in glycerol 20 g/L
Uv (vis) Spectroscopy maximum 267,3 nm

1.6. Uses of Saccharin

Saccharin is in the form of an acid and also as calcium-or sodium salt, used in food
manufacturing, mainly the salt, due to its high solubility in water [13]. There is no
considerable difference in the sweetness of the various forms; the intensity of sweetness for
each derivative is ranging about 300-800 times greater than that of sucrose and dependent on
concentration and other factors. As with most other sweeteners, there is an inverse
relationship between sweetening intensity and concentration, compared to a sucrose-solution.
For example, a 1%-saccharin-solution is approximately eight hundred times sweeter, while a
3%- sucrose solution is only five hundred times as sweet as a sucrose-solution. The
sweetening intensity of saccharin depends on concentration and also on the composition of
the solution [14]. A great value of sweetening intensity can be noticed in a combination of
saccharin and other sweeteners, more than just the additive values of every component. In
addition, mixing up various sweeteners will lead to the taste modification; even small
amounts of additional sweeteners can reduce the slight bitter metallic aftertaste of saccharin
considerably [14]. For that, the food industry often uses saccharin combined with aspartame,
cyclamate, thaumatine or xylit [15]. Since saccharin is excreted unchanged mostly through
urine, it is most appropriate for diabetic persons or overweight individuals as a sugar
substitute [13]. The recommended maximum everyday dose is equal 5mg/kg body weight
[15]. Even though saccharin is surely most well-liked as food additive E954, it also presents
in other sectors: in cosmetics, toothpaste and mouthwash, pharmaceuticals, cigarettes, as a
flavoring agent in pig feed and even as a brightener in anticorrosive nickel coatings. [14].

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1.7 Ingestion
Saccharin, when ingested, actually goes through the human GIT without being digested. The
experimental models revealed that the saccharin is not absorbed or metabolized [16 ̶ 18]. It is
excreted and unmoved via the kidneys. Saccharin has zero energy. It was banned in the
United States by the US FDA. It can stimulate the release of insulin in humans. It was only
artificial sweetener presented in the rats because of its taste [19].

1.8. Absorption
Saccharin's absorption depends on different factors including the pKa and the pH values of
the animal. The absorption of saccharin occurs with a pKa of about 2.0- 2.2. The unionized
species found in acidic media which is completely absorbed form in many of animal species.
While, in the stomach of the rabbit and guinea-pig, saccharin is absorbed completely when the
pH come to 1.9 and 1.4, respectively. as it is compared to the stomach of rat, the pH equal to
4.2. The pH of the stomach and extent of absorption in monkeys and man are in-between
those of the rabbit and guinea-pig on one side, and the rat on the other. The extent of
saccharin absorption depends mainly on food intake that affects the acidity of the stomach
contents [20].

1.9. Distribution and Excretion

Researchers used radioactivity to observe the distribution of radioactive-saccharin in
organs and tissues of rats at different time intervals (one, two, four, eight, twenty-four, forty
eight and seventy-two h), following a single oral administration of labeled saccharin (3-14C)
,(0.2 mg/kg), nearly 1 h after dosing, a trace of radioactivity was found in approximately all
organs. Small quantities of 14C was found in spleen and brain. While the highest amount of
14
C was established in urinary bladder, liver, and kidney, which reached a maximum at four
and eighth. In the next research, bladders of the treated rats were washed with 8, 0.5 ml
portions of a 0.9% saline solution, a significant portion of the labeled 14C activity was found
to be concentrated in the bladder tissue [21].

1.10. Metabolism of Saccharin

A research work carried out in metabolism of saccharin has shown that saccharin, an
efficient sweet taste agonist, does not undergo detectable metabolism in each animal or
human being. Whereas, saccharin (84%) principally was excreted within the urine and about
40% of the dose was recovered from the feces after dosing 24h, traces of administered
saccharin radioactivity stayed in different tissue after 3 days including heart, liver, pancreas,
adrenals, thymus, and testes. Previous metabolic studies have shown that activating either
sweet taste receptors (taste receptors family 1 [T1Rs]), or bitter taste receptors (taste receptors
family [T2Rs]) on taste receptor cells (TRCs) by sweet, umami, or sour compounds initiates a
common signaling cascade. Saccharin can stimulate signaling cascade associated with taste
receptors (sweet, T1R2 þ T1R3; bitter, T2R43/T2R44) and their heterotrimeric G protein
gustducin (consisting of Ga and Gbc subunits), to trigger Ca2þ signaling pathways and affect
cAMP levels in taste cells. T1R3 or Ga knockout mice indicated a distinctly reduced
preference for saccharin. New T1Rs and their downstream protein Ga are detected beyond the
taste buds [22].
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1.11. Toxicity Study of Saccharin
Saccharine is similar to aspartame, acesulfame K, and cyclamates. Saccharine -300 times
sweeter than sucrose- is normally used in many foods like soft drinks, baked goods, jams,
canned fruits, candy, salad dressings, dessert, etc, since saccharin is utilized by a lot of
people. Safety of saccharin is essential for public health. Also, many works have been done to
ensure the safety of saccharin [23]. Carried out since patients with serious diabetes, cancer,
and liver damage, who consume artificial sweeteners with drugs. Such interaction may have
an effect on drug metabolism. The research work showed the effects of the possible saccharin,
and medication interaction on the activities of five cytochrome P450 enzymes (CYPs) in male
ICR mice. Another research work examined the significant effects of saccharin dose, equal
4,000 mg/kg using the medication bupropion after pretreatment of mice within saccharin for
seven days, and after simultaneous administration of both bupropion and saccharin. The
results established that saccharin did not have a considerable effect on the five CYPs in the S9
fractions obtained from the liver of mice. Also, there were no obvious differences in the
pharmacokinetics factors of bupropion between the control and the pretreated groups with
saccharin, and that receiving associated administration of saccharin. Thus, the results
documented the safety of saccharin, and it has very low hazard of saccharin-drug interaction
[24].

1.11.1. Carcinogenicity Study

Saccharin is still considered as a diabetic and carcinogen inducer in several parts of the
world. In 1977, after the publication work a high rate of bladder cancer was reported in rats
administered with large doses of saccharin. Canada banned saccharin however US-FDA also
suggested a ban. All saccharin-containing foods showed a warning label alerting that
saccharin can be carcinogenic. The teratological, hepatotoxicity, genotoxicity and
carcinogenicity studies of saccharin in animals containing humans were conducted by the
most profoundly important global health and credible science organizations worldwide. Their
results showed no evidence to prove a causal association among saccharin consumption and
health risks in humans at usual dosage. The US-FDA officially withdrew its 1977 suggestion
to prohibit the saccharin’s use, and the National Toxicity Program advertised the unsafe of
saccharin as a carcinogen.
Therefore, saccharin can be used safely and results in a good physical shape lifestyle without
accumulation of calories, or the risk of obesity due its associated cardiovascular problems
[25].
Urinary bladder carcinogenesis can be promoted by sodium saccharin and sodium ascorbate
in rats when they fed at high doses of sodium saccharin. It increases epithelial proliferation in
short-term assays. While the free acid forms lack either promoting or cell proliferating
inducing activity. When the researcher set up an experiment to compare the tumor-promoting
activity of various types of saccharin, and to estimate the role in urinary sodium, pH, and
calcium promotion, in addition to other factors [26].
Saccharin does not increase the risk of bladder cancer in humans. [24]. It was considered in
all literature about saccharine safety. Work on saccharin carcinogenicity appears to be
mystifying, as shown in Table 2.

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Table 2. Shows the Carcinogenicity of saccharin happening in animals’ models.

Test material Carcinogenicity Results References

model
Male and female Charles River rats Bladder tumors - Munro et al. [25 ]
Male and female Charles River Bladder tumors + Howe et al. [26]
rats Bladder tumors + Reuber [27]
Rats and mice Bladder tumors - Risch et al. [28]
Rats and mice Bladder tumors - Morgan and Wong [29]
Rats and mice Bladder tumors + Zurlo and Squire [30]
Rats & Monkey Bladder tumors - Takayama et al. [31]

Footnote: + (Positive), - (Negative)

1.11.2. Toxicological Study

Saccharin has the possibility to induce cancer in rats and dogs, therefore, in1911, there was
the first attempt to ban saccharin, when a group of researchers identified it, for example, an
“adulterant” not appropriate for common use in foods. Later on, the same group workers
permitted its use in products for patients. At the time of Arnold’s publication, there were only
three studies of saccharin, used a two-generation model. The investigations established that
when rats were exposed to diets containing 5% or 7.5% saccharin from the time of conception
to death, a significantly increased frequency of urinary bladder cancers was shown, generally
in males. The fact that saccharin is considered to be as a nucleophilic agent, and cannot bind
DNA. Therefore, saccharin is not metabolized, but it does destroy humeral antibody
production in rats. Using a dose of 5% or more, saccharin does not function as a distinctive
harmful carcinogen. Theoretically, all carcinogens are considered as a strong electrophilic
agent [32].

1.11.3. Genotoxicity Study

Induction of chromosomal aberrations in Chinese hamster cells and human lymphocytes,
in-vitro studies for sodium saccharin was found weakly positive.
Weak responses were noticed in some in-vitro assays at the chromosomal level. While
elevated concentrations maybe due to ionic imbalances that are well believed to cause non-
specific effects. There are also conflicting reports from in vitro work , but in certain cases, the
materials used were found to contain impurities raised from the manufacture of
saccharin.[33]. It was studied that all literature about saccharine safety. As said by the
research, genotoxicity is displayed in Table 3.

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Table 3. Sum of the genotoxicity of saccharin.

Test material Genotoxic end- point Results References

lymphocytes Sister chromatid

Human + Zhang et al. [34]
exchanges

Plant Sister chromatid exchanges + Zhang et al. [34]

F344 and Sprague-

Rat hepatocyte DNA repair assay - Jeffrey and Williams [35]
Dawley rats

glandular stomach, colon, liver, kidney, +(glandular

Male ddY mice
stomach
urinary bladder, lung, brain, and bone
Sasaki et al. [36]
marrow and colon)

comet assay

Bandyopadhyay et al.
Salmonella typhimurium Ames -
[37]

Bandyopadhyay et al.
Swiss albino mice Comet assay +
[37]

Fish sperm DNA DNA binding affinity +/- Icsel and Yılmaz [38]

Human leukocytes Alkaline and neutral comet assays - Frenzilli et al [39]

Footnote: + (Positive), - (Negative)

1.11.4. Epidemiological Study

The epidemiological studies showing a proof concerning on saccharin, indicated there was
no noticeable relationship among artificial sweetener consumption mostly known saccharin,
and bladder cancer in humans. Diverse epidemiological studies designated no increase in the
frequency of bladder tumors in human from the consumption of saccharin, including in
persons with the elevated use of artificially sweetened beverages and persons using saccharin.
[22] The literature carcinogenicity of saccharine in epidemiological studies was still
confusing, as displayed in Table 4.

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Table 4. Sum of the carcinogenicity of saccharin in epidemiological studies.

Study design Carcinogenicity model Results References

Human Bladder - Armstrong and Doll [40]

Human Bladder - Jensen and Kamby [41]

1953 cases and 4154 controls Colorectum - Francheschi et al. [42]

254 bladder cancer patients Bladder + Yu et al. [43]

and254 Controls

598 cases and 1491 controls Oral cavity and pharynx - Francheschi et al. [44]

304 cases and 743 controls Oesophagus - Bosetti et al. [45]

1031 cases and 2411 controls Ovary] - Bosetti et al. [46]

460 cases and 1088 controls Larynx - Bosetti et al. [47]

2569 cases and 2588 controls Female breast - Tavani et al. [48]

1294 cases and 1451 controls Prostate - Bosetti et al. [49]

767 cases and 1534 controls Renal cell - Bravi et al. [50]

51 patients and 87 controls Urinary tract + Andreatta et al. [51]

230 patients and 547 controls stomach - Bosetti et al. [52]

326 patients and 652 controls pancreas - Bosetti et al. [52]

454 patients and 908 controls endometrium - Bosetti et al. [52]

Footnote: + (Positive), - (Negative)

1.11.5. Hepatotoxicity Study

In 1992, Kumar et al. documented the favorable use of saccharin. It is reported that
saccharin is safe to liver function [53]. Several generations of Americans have made the use
of saccharin, supporting its role in the pathogenesis of liver damage. an essential part of their
everyday lifestyle in the united patients. Saccharin is not metabolized in any number of
healthy consumers to support the use of a non- vivo, being almost unchanged in the urine, and
its caloric sweetener similar to saccharin for weight reduction, and doesn't accumulate in the
liver. The small amount of diabetic persons, saccharin (never exceeding sixteen mg/day) were
taken by patients marks the idiosyncratic reaction [54].

1.12. Synthesis of Saccharin Derivatives

N-[4-(Dicyanomethylazo) phenyl]-2- saccharin-2-ylacetamide (13) showed to be a suitable
precursor for the preparation of different pyridazine and pyrimidine derivatives15a, b, 17 and
18 as depicted in the Scheme 3. [55].

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Scheme 3. Synthesis of different saccharin derivatives.

Reagents and conditions: (i) CH2(CN)2, Ethyl alcohol, Sod. acetate; (ii) XCH2Y, Ethyl alcohol,
Et3N; (iii) 2CH2(CN)2, EtOH, Et3N; (iv) H2NCXNH2, Sod.ethoxide.
The reaction of saccharin and tryptophan occurred readily at room temperature in aqueous
solution to produce a compound separated at pH 5.5 in a 1:1 ratio as shown in Scheme 4.
[56].

Scheme 4. Schiff-base formation from the reaction of tryptophan and saccharin.

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2-(Pyridine-4-yldiazonium) isoindoline-1-one-3-sulphoxide (22) resulted from the coupling
reaction of 4-(chloridediazeayl) pyridine (21) with sodium saccharin(6a) in DMF, Scheme 5.
[57].

Scheme 5. Synthesis of 2-(pyridine-4-yldiazonium) isoindoline-1-one-3-sulphoxide.

Sulfonphthalein can be synthesized in a single pot by treatment of saccharin and phenol

through the in-situ preparation of 2-sulfobenzoic anhydride, subsequently its reaction with
phenol by using H2SO4 as the condensing agent, in the absence of any solvent, Scheme 6.
[58].

Scheme 6. Synthesis of phenol sulfonephthalein from saccharin and phenol: (a) conc. H2SO4 = oleum, 140 °C, 3
h; (b) phenol, conc. H2SO4, 140 °C, 3 h.

A new Schiff base was produced by the reaction of the transition metal complexes of Cobalt
(II), Nickel (II), Copper (II), Zinc (II) and Cadmium(II) with (3E)-3-{(2E)-[(3-hydroxy-6-
methyl-3, 4,6,8atetrahydroquinoxalin-2-yl) methylidene ]hydrazinylidene}-3H-1,2-
benziothiazol-2-ide1,1-dioxide were prepared, as shown in Scheme 7. [59].

Scheme7. Synthesis of new Schiff base from metal complexes.

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Schiff bases (30, 31 and33) can be synthesized by reaction of a compound (29) with
NH2NH2.H2O, and glacial acetic acid. Compound (34) has been produced by a reaction of a
compound (29) with phenyl isothiocyanate by using triethylamine as catalyst. Finally,
compound (32) can be obtained by the reaction of a compound (29) with NH2NH2.H2O in the
presence of NaOAc or, NaOH, as shown in the Scheme 8. [60].

Scheme 8. Synthesis of saccharin derivatives (30-34) by reaction N-1,3-benzothiazole-2-yl-2-chloroacetamide-

2-amimobezothiazo with different compounds.

The reaction of saccharin with ethylene diamine in presence few drops glacial acetic acid,
produced compound (35). Acetylation of compound (36) produced a compound (39).
Reaction of compound (35) with ethyl acetoacetate afforded pyrazole, and pyranopyrazole
derivatives (37, 38), respectively, as shown in Scheme 9.

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Scheme 9. Synthesis of saccharin derivatives (36-39) by reaction of saccharin with different reagents.

Also, the reaction of sodium saccharin with halo compounds afforded some of N-alkyl
saccharin derivatives (40-47). Condensation of ethylene diamine with compounds (40,44) in
presence few drops glacial acetic acid (GAA) produced compounds (48,49) as shown in
Scheme 10. [61]

Scheme10. Synthesis of N-alkyl saccharin derivatives (40-49) by reaction of sodium saccharin with halo
compounds.

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1.13.1. Photo isomerization of Saccharin
Regarding the photochemistry of benzisothiazoles, a literature survey reveals that the
information available is restricted to photolysis in solution. Previous work on the
photochemistry of N-propylsaccharin (2, 3) confirmed that photolysis led to cleavage of the
S−N bond, eventually leading to the formation of benzamide through extrusion of SO2, as
shown in Scheme 11.

Scheme 11. Synthesis of benzamide.

Photochemistry of 3,3-di-substituted 2,3-dihydro-1,2-benzisothiazole 1,1-dioxides in

methanol and acetonitrile. Three reaction routes were detected in two cases: an initial S−N
hemolysis, as shown in Scheme 12.

Scheme 12. Photochemistry of 3,3- substituted 2,3-dihydro-1,2-benzisothiazole 1,1-dioxides.

Saccharyl system photo isomerization implies photo induced hemolysis of the S−N bond,
then a delocalized bi radical is produced in the amide moiety, upon rotation around the
exocyclic C−C bond, furnished the iso-saccharin through ring closure, as shown in Scheme
13. [62].

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Scheme 13. Photoisomerization reaction observed for saccharin.

2. Conclusion
Saccharin safety has been reviewed and certified by the Joint Expert Committee on Food
Additives (JECFA) of the World Health Organization and the Scientific Committee for Food
of the European Union. Saccharin is permitted in many hundred countries around the world. It
can be advocated as one of the very best choices for diabetic person and those dieting. The
use of saccharin as it is free of calorie, safe and brings a well physical shape lifestyle state.
While accumulation and the hazard of obesity within its related cardiovascular aggravations
literature reports on genotoxicity and carcinogenicity of saccharine is still confusing.
Therefore, persons should be careful to the consumption of this artificial sweetener.

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